Previous studies have suggested that interleukin-6 (IL-6)-induced pro-inflammatory environments in the vascular endothelium are critical for the initiation and development of atherosclerosis. Our recent findings have provided new evidence to indicate that interleukin-4 (IL-4) can directly induce IL-6 expression, which raise the possibility that IL-6 may play a critical role in IL-4-mediated inflammatory pathways in vascular endothelium. The molecular signaling mechanisms of IL-4-induced IL-6 expression, however, remain poorly defined. In the proposed project, we hypothesize that IL-4 may induce inflammatory pathways in vascular endothelium through the p38 MAPK-mediated up-regulation of IL-6 expression. The specific aims to study this hypothesis include (1) examining whether IL-4 induces IL-6 expression and inflammatory environment through antioxidant-sensitive mechanisms in vascular endothelium, (2) determining the molecular regulatory mechanisms of IL-4-induced IL-6 expression in vascular endothelium, and (3) elucidating the p38 MAPK-mediated signaling pathways responsible for IL-6 induction in IL-4-stimulated vascular endothelium. In order to achieve these goals, we will define the cellular and molecular basis of IL-4-mediated progression of atherosclerosis by investigation of its effects on IL-6 expression and inflammatory reactions in vascular endothelium in both cell culture and experimental animal model systems. We will also investigate the redox-regulated mechanisms of IL-4-induced pro-inflammatory pathways to identify antioxidants as a potential preventive and/or therapeutic approach. Furthermore, the proposed project will focus on the p38 MAPK-mediated molecular signaling mechanisms of IL-4-induced IL-6 expression both in vivo and in vitro. The proposed studies will advance present understanding of cellular and molecular signaling mechanisms of IL-4-mediated pro-inflammatory pathways and its protection. Results may also contribute to the development of new opportunities for diagnostic and therapeutic interventions for mitigating atherosclerotic lesion development. Additionally, the proposed research project will make a special effort to stimulate biomedical research by both undergraduate and graduate students. In particular, it is anticipated that undergraduate students involved in the proposed studies will benefit from exposure to and active participation in biomedical research project and be encouraged to pursue graduate studies in the health sciences. 7. Project Narrative Cardiovascular disease caused by atherosclerosis is the number 1 cause of death and disability in the United States, and the pro-oxidative and pro-inflammatory pathways within vascular endothelium have been implicated in the initiation and progression of atherosclerosis. The proposed studies will contribute to a better understanding of the cellular and molecular mechanisms of interleukin-4-mediated novel inflammatory pathways leading to the development of atherosclerosis. More importantly, it will help develop new therapeutic approaches to translate these basic laboratory discoveries into clinically effective treatments for over 50 million Americans at cardiovascular risk. [unreadable] [unreadable] [unreadable]